All physiological systems experience age-associated decrements in function that can be described as primary aging. There is mounting evidence that many of these changes can be delayed or even prevented by long-term caloric restriction (CR). In humans, the first experiments on the effect of energy restriction were performed by Keys et.al in the 1950s. In these classic experiments, lean volunteers consumed 50% of their habitual caloric intake. There was a decrease in basic metabolic rate when adjusted for body surface area, body weight, and cell mass. However, there were also indications of malnutrition with deficiencies in many micronutrients. Beyond this experiment, most information comes from animal models, and significant CR benefits have been observed. In 2001 and 2002, the National Institute on Aging (NIA) issued Requests for Application to perform detailed clinical studies into the effects of CR in humans. The stated purpose was,... to gain knowledge about the effects in humans of sustained CR on physiology, metabolism, body composition, risk factors for age-related pathologies ... and its potential adverse effects. Phase 1 of the program has been completed, and following a detailed and comprehensive developmental process, the Phase 2 study has begun. Power calculations indicate that to address the primary study outcomes, as well as important secondary and exploratory outcomes, 250 participants should be enrolled. By March 2009, however, we anticipate randomizing only 170 participants. The present application therefore requests funding to complete the Phase 2 study with the full complement of 250 participants. The Specific Aims are: (1) maintain statistical power for the two primary outcomes at the originally planned levels; (2) increase statistical power for important secondary and exploratory outcomes to more acceptable levels relative to a study with only 150 enrolled; (3) complete enrollment of volunteers into the Phase 2 study in an expeditious manner and minimize participant drop-out; (4) undertake detailed procedures to safeguard the fidelity of the intervention and maintain quality control over the outcome determinations; (5) store biological samples in a central repository, and provide opportunities for mechanistic studies by the greater scientific community; and, (6) perform detailed statistical analyses. RELEVANCE (See instructions): CALERIE is the first comprehensive study to determine whether the salutary effects of caloric restriction observed in animal studies extend to human beings. Ultimately, CALERIE will further our knowledge of the basic biology of the human aging process. It may also contribute to development of practical strategies for retardation of aging and age-related diseases.